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Biomedical subjects

C Heidelberger

Publications and source records attributed to C Heidelberger.

At least 91 records · Page 5Linked to original sources
PubMed1975

Reversion of the 8-azaguanine resistant phenotype of variant Chinese hamster cells treated with alkylating agents and 5-brono-2'-deoxyuridine.

From cultures of V79 Chinese hamster cells, 10 independent clones of 8-azaguanine resistant cells were isolated and subcultured. Cells from all ten clones were resistant to 1 mg/ml levels of 8-azaguanine (8-AzG), contained less than 3% of the wild type levels of the enzyme, hypoxanthine guanine phosphoribosyl transferase (HGPRT), and were unable to grow in HAT medium. The ten clones were classified according to the conditions under which they reverted to the wild type phenotype. Clones in classes I and II reverted spontaneously with frequencies of 40-10(-5) and about 3-10(-5) respectively, and the reversion frequency was independent of the density of cells of all but one of the clones in the culture medium used. Class II clones evinced increased reversion frequencies with ethyl methanesulfonate (EMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), and to a lesser extent with 5-bromo-2'-deoxyuridine (budR), suggesting that these clones contained point mutations in a locus which controls HGPRT activity. The processes of reversion and toxicity appeared to be associated. Class III clones did not revert spontaneously or with BUdR and MNNG, but did revert with EMS. The reversion frequency of class I clones was not increased after treatment with EMS, MNNG or BUdR.

Alkylating Agents↗
PubMed1975

Cyclopenta[f]isoquinoline derivatives designed to bind specifically to native deoxyribonucleic acid. 1. Synthesis of 3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline.

By the use of space-filling models, a novel compound, 6-carbamylmethyl-8-methyl-7(5)H-cyclopenta[f]isoquinolin-3-(2H)-one was devised which would be expected to hydrogen bond specifically to GC pairs in the major groove of the double helix such that (i) the amino group of the cytosine molecule donates a hydrogen bond to the C-3 carbonyl of the isoquinoline moiety and (ii) the amide proton of the side chain donates a hydrogen bond to the N-7 of guanine. 3-Ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (4) which constitutes the basic ring system of 1 was synthesized in a multistep procedure starting from m-methyl-N-acetylbenzylamine (5). Friedel-Crafts reaction of 5 led to 2,4-bis(chloromethyl)-5-methyl-N-acetylbenzylamine (6) which on treatment with KCN, hydrolysis of the resultant nitrile, and subsequent esterification afforded 6-carbethoxymethyl-7-methyl-1,2,3,4-tetrahydroisoquinolin-3-one (9). Treatment of 9 with triethyloxonium fluoborate followed by dehydrogenation of the product gave 6-carbethoxy-methyl-3-ethoxy-7-methylisoquinoline (14). Chain extension of 14 followed by cyclization led to 3-ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (19) which on reduction and subsequent dehydration yielded 3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (4).

Binding Sites↗
PubMed1975

Cyclopenta[f]isoquinoline derivatives designed to bind specifically to native deoxyribonucleic acid. 2. Synthesis of 6-carbamylmethyl-8-methyl-7(5)H-cyclopenta[f]isoquinolin-3(2H)-one and its interaction with deoxyribonucleic acids and poly(deoxyribonucleotides).

3-Ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (2) was converted to 6-carbethoxymethyl-3-ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (6) through an oxalyl derivative. Treatment of 6 with ammonia gave the corresponding amide 7 which on sodium borohydride reduction and subsequent dehydration yielded 6-carbamylmethyl-3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (9). The analogous ester 10 was similarly obtained from 6. Numerous attempts to dealkylate the 3-ethoxy group of 9 or 10 failed. However, 6 coould easily be dealkylated on heating with 25% hydrochloric acid in a sealed tube.The ester, 6-carbethoxymethyl-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinoline-3(2H),5-dione (11), so obtained was converted to the corresponding amide 12 which on reduction with sodium borohydride and subsequent dehydration afforded the desired compound, 6-car-bamylmethyl-8-methyl-7(5)H-cyclopental[f]isoquinolin-3-(2H)-one (1). 1 was found to be mildly cytotoxic againstL5178Y mouse leukemia cells in culture.1 was also found to bind to native calf thymus DNA. 1 inhibited RNA synthesis by a DNA-dependent RNA polymerase and a higher inhibition of RNA synthesis was observed when poly(dG-dC) was used as a template than when poly(dA-dT) was used. A significant increase of thermal transition temperature of calf thymus DNA and poly(dG)-poly(dC) was observed in the presence of 1. The accumulated evidence demonstrates that 1 interacts weakly with calf thymus DNA and interacts preferentially with poly(deoxyribonucleotides)-containing GC pairs.

Animals↗
PubMed1975

The isolation and characterization of polycyclic hydrocarbon-binding proteins from mouse liver and skin cytosols.

The major protein to which metabolites of methylcholanthrene are covalently bound has been purified from C3H mouse liver cytosol. Its properties are identical to the mouse skin h-protein, which may be primary arget of carcinogenic hydrocarbon metabolites during transformation to caner. It has a molecular wight of 44,000, consists of 2 subunits o- M.W. 20,000, has an isoelectric point (pI) of 8.05 to 8.6, and a sedimentation coefficient of 3.6 S. These physical properties are rather similar to those of ligandin, a hepatic protein that binds carcinogen metabolites, steroid anionic metabolites, bilirubin, and exogenous organic anions, but not to those of the rat liver azo dye carcinogen binding 'slow h-2-5S' protein. The h-protein and ligandin consistently give different pl values. Two minor basic proteins (molecular weights around 44,000 each), to whcih methylcholanthrene metabolites are convalently bound, have been separated from the h-protein by carboxymethyl-cellulose chromatography. Prelininary results indicate that these 2 minor proteins are related to ligandin. A protein to which methylcholanthrene is noncovalently bound was also identified in the acidic fraction of the mouse liver and skin sytosols and has been partially purified and characterized. It has a molecular weight of 60,000, a pl of 5.0, and a sedimentation coefficient of 4.5S.

Animals↗
PubMed1975

Neoantigens on chemically transformed cloned C3H mouse embryo cells.

Using an in vitro cytotoxicity test for cell-mediated immunity and a membrane immunofluorescence test, the appearance of new antigens was detected on cloned C3H mouse embryo cells undergoing malignant transformation in vitro following treatment with 3-methylcholanthrene or 7,12-dimethylbenz[a]anthracene. These antigens were recognized by specifically immunized syngeneic mice and were individually unique for each of eight chemically transformed cell lines tested, all of which were derived from the same control parent clone. Very few cross-reactions were seen between lymphoid cells or antibody from mice immunized against a given cell line and target cells of other cell lines. New antigens could not be detected on two spontaneously transformed lines. Lymphoid cells from multiparous pregnant or embryo-immunized cmice were used to search for fetal antigens on control and transformed cells. Fetal antigens were detected on seven of the chemically transformed cell lines and one spontaneous transformant, but not on nontransformed control cells. It is concluded that individually specific new antigens are characteristic of chemically transformed cells, but the expression of fetal antigens may be a more common feature of transformed cells in general.

9,10-Dimethyl-1,2-benzanthracene↗